Binge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease

Alcohol-related liver disease (ARLD) represents a major public health burden. Identification of high-risk individuals would allow efficient targeting of public health interventions. Here, we show significant interactions between pattern of drinking, genetic predisposition (polygenic risk score, PRS) and diabetes mellitus, and risk of incident ARLD, in 312,599 actively drinking adults in UK Biobank. Binge and heavy binge drinking significantly increase the risk of alcohol-related cirrhosis (ARC), with higher genetic predisposition further amplifying the risk. Further, we demonstrate a pronounced interaction between heavy binge drinking and high PRS, resulting in a relative excess risk due to interaction (RERI) of 6.07. Diabetes consistently elevates ARC risk across all drinking and PRS categories, and showed significant interaction with both binge patterns and genetic risk. Overall, we demonstrate synergistic effects of binge drinking, genetics, and diabetes on ARC, with potential to identify high-risk individuals for targeted interventions

Binge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease

Alcohol-related liver disease (ARLD) represents a major public health burden. Identification of high-risk individuals would allow efficient targeting of public health interventions. Here, we show significant interactions between pattern of drinking, genetic predisposition (polygenic risk score, PRS) and diabetes mellitus, and risk of incident ARLD, in 312,599 actively drinking adults in UK Biobank. Binge and heavy binge drinking significantly increase the risk of alcohol-related cirrhosis (ARC), with higher genetic predisposition further amplifying the risk. Further, we demonstrate a pronounced interaction between heavy binge drinking and high PRS, resulting in a relative excess risk due to interaction (RERI) of 6.07. Diabetes consistently elevates ARC risk across all drinking and PRS categories, and showed significant interaction with both binge patterns and genetic risk. Overall, we demonstrate synergistic effects of binge drinking, genetics, and diabetes on ARC, with potential to identify high-risk individuals for targeted interventions

Alcohol intake and cause-specific mortality: conventional and genetic evidence in a prospective cohort study of 512 000 adults in China

Background Genetic variants that affect alcohol use in East Asian populations could help assess the causal effects of alcohol consumption on cause-specific mortality. We aimed to investigate the associations between alcohol intake and cause-specific mortality using conventional and genetic epidemiological methods among more than 512 000 adults in China. Methods The prospective China Kadoorie Biobank cohort study enrolled 512 724 adults (210 205 men and 302 519 women) aged 30–79 years, during 2004–08. Residents with no major disabilities from ten diverse urban and rural areas of China were invited to participate, and alcohol use was self-reported. During 12 years of follow-up, 56 550 deaths were recorded through linkage to death registries, including 23 457 deaths among 168 050 participants genotyped for ALDH2-rs671 and ADH1B-rs1229984. Adjusted hazard ratios (HRs) for cause-specific mortality by self-reported and genotype-predicted alcohol intake were estimated using Cox regression. Findings 33% of men drank alcohol most weeks. In conventional observational analyses, ex-drinkers, non-drinkers, and heavy drinkers had higher risks of death from most major causes than moderate drinkers. Among current drinkers, each 100 g/week higher alcohol intake was associated with higher mortality risks from cancers (HR 1·18 [95% CI 1·14−1·22]), cardiovascular disease (CVD; HR 1·19 [1·15−1·24]), liver diseases (HR 1·51 [1·27−1·78]), non-medical causes (HR 1·15 [1·08−1·23]), and all causes (HR 1·18 [1·15−1·20]). In men, ALDH2-rs671 and ADH1B-rs1229984 genotypes predicted 60-fold differences in mean alcohol intake (4 g/week in the lowest group vs 255 g/week in the highest). Genotype-predicted alcohol intake was uniformly and positively associated with risks of death from all causes (n=12 939; HR 1·07 [95% CI 1·05−1·10]) and from pre-defined alcohol-related cancers (n=1274; 1·12 [1·04−1·21]), liver diseases (n=110; 1·31 [1·02−1·69]), and CVD (n=6109; 1·15 [1·10−1·19]), chiefly due to stroke (n=3285; 1·18 [1·12–1·24]) rather than ischaemic heart disease (n=2363; 1·06 [0·99–1·14]). Results were largely consistent using a polygenic score to predict alcohol intake, with higher intakes associated with higher risks of death from alcohol-related cancers, CVD, and all causes. Approximately 2% of women were current drinkers, and although power was low to assess observational associations of alcohol with mortality, the genetic evidence suggested that the excess risks in men were due to alcohol, not pleiotropy. Interpretation Higher alcohol intake increased the risks of death overall and from major diseases for men in China. There was no genetic evidence of protection from moderate drinking for all-cause and cause-specific mortality, including CVD. Funding Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Wellcome Trust, Medical Research Council, and Chinese Ministry of Science and Technology

Associations of alcohol intake with subclinical carotid atherosclerosis in 22,000 Chinese adults

Background and aims We investigated the causal relevance of alcohol intake with measures of carotid artery thickness and atherosclerosis in Chinese adults. Methods The study included 22,384 adults from the China Kadoorie Biobank, with self-reported alcohol use at baseline and resurvey, carotid artery ultrasound measurements, and genotyping data for ALDH2-rs671 and ADH1B-rs1229984. Associations of carotid intima media thickness (cIMT), any carotid plaque, and total plaque burden (derived from plaque number and size) with self-reported (conventional analyses) and genotype-predicted mean alcohol intake (Mendelian randomisation) were assessed using linear and logistic regression models. Results Overall 34.2% men and 2.1% women drank alcohol regularly at baseline. Mean cIMT was 0.70 mm in men and 0.64 mm in women, with 39.1% and 26.5% having carotid plaque, respectively. Among men, cIMT was not associated with self-reported or genotype-predicted mean alcohol intake. The risk of plaque increased significantly with self-reported intake among current drinkers (odds ratio 1.42 [95% CI 1.14–1.76] per 280 g/week), with directionally consistent findings with genotype-predicted mean intake (1.21 [0.99–1.49]). Higher alcohol intake was significantly associated with higher carotid plaque burden in both conventional (0.19 [0.10–0.28] mm higher per 280 g/week) and genetic analyses (0.09 [0.02–0.17]). Genetic findings in women suggested the association of genotype-predicted alcohol with carotid plaque burden in men was likely to due to alcohol itself, rather than pleiotropic genotypic effects. Conclusion Higher alcohol intake was associated with a higher carotid plaque burden, but not with cIMT, providing support for a potential causal association of alcohol intake with carotid atherosclerosis

Alcohol consumption and risks of more than 200 diseases in Chinese men

Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the associations of alcohol consumption with 207 diseases in the 12-year China Kadoorie Biobank of >512,000 adults (41% men), including 168,050 genotyped for ALDH2-rs671 and ADH1B-rs1229984, with >1.1 million ICD-10 coded hospitalized events. At baseline, 33% of men drank alcohol regularly. Among men, alcohol intake was positively associated with 61 diseases, including 33 not defined by the World Health Organization as alcohol-related, such as cataract (n = 2,028; hazard ratio 1.21; 95% confidence interval 1.09–1.33, per 280 g per week) and gout (n = 402; 1.57, 1.33–1.86). Genotype-predicted mean alcohol intake was positively associated with established (n = 28,564; 1.14, 1.09–1.20) and new alcohol-associated (n = 16,138; 1.06, 1.01–1.12) diseases, and with specific diseases such as liver cirrhosis (n = 499; 2.30, 1.58–3.35), stroke (n = 12,176; 1.38, 1.27–1.49) and gout (n = 338; 2.33, 1.49–3.62), but not ischemic heart disease (n = 8,408; 1.04, 0.94–1.14). Among women, 2% drank alcohol resulting in low power to assess associations of self-reported alcohol intake with disease risks, but genetic findings in women suggested the excess male risks were not due to pleiotropic genotypic effects. Among Chinese men, alcohol consumption increased multiple disease risks, highlighting the need to strengthen preventive measures to reduce alcohol intake

Individual and interpersonal triggers to quit smoking in China:a cross-sectional analysis

Aims: To determine the most prominent individual and interpersonal triggers to quit smoking in China and their associations with sociodemographic characteristics. / Methods: Data come from Waves 1–3 (2006–2009) of the International Tobacco Control (ITC) China Survey, analysed cross-sectionally as person-waves (N=14 358). Measures included sociodemographic and smoking characteristics. Those who quit between waves (4.3%) were asked about triggers that ‘very much’ led them to stop smoking, and continuing smokers about triggers that ‘very much’ made them think about quitting. Triggers covered individual (personal health concerns, cigarette price, smoking restrictions, advertisements, warning labels) and interpersonal factors (family/societal disapproval of smoking, setting an example to children, concerns about secondhand smoke). / Results: Over a third of respondents (34.9%) endorsed at least one trigger strongly; quitters were more likely than smokers to mention any trigger. While similar proportions of smokers endorsed individual (24.4%) and interpersonal triggers (24.0%), quitters endorsed more individual (61.1%) than interpersonal (48.3%) triggers. However, the most common triggers (personal health concerns; setting an example to children) were the same, endorsed by two-thirds of quitters and a quarter of smokers, as were the least common triggers (warning labels; cigarette price), endorsed by 1 in 10 quitters and 1 in 20 smokers. Lower dependence among smokers and greater education among all respondents were associated with endorsing any trigger. / Conclusions: Individual rather than interpersonal triggers appear more important for quitters. Major opportunities to motivate quit attempts are missed in China, particularly with regard to taxation and risk communication. Interventions need to focus on more dependent and less-educated smokers

Binge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease

AbstractAlcohol-related liver disease (ARLD) represents a major public health burden. Identification of high-risk individuals would allow efficient targeting of public health interventions. Here, we show significant interactions between pattern of drinking, genetic predisposition (polygenic risk score, PRS) and diabetes mellitus, and risk of incident ARLD, in 312,599 actively drinking adults in UK Biobank. Binge and heavy binge drinking significantly increase the risk of alcohol-related cirrhosis (ARC), with higher genetic predisposition further amplifying the risk. Further, we demonstrate a pronounced interaction between heavy binge drinking and high PRS, resulting in a relative excess risk due to interaction (RERI) of 6.07. Diabetes consistently elevates ARC risk across all drinking and PRS categories, and showed significant interaction with both binge patterns and genetic risk. Overall, we demonstrate synergistic effects of binge drinking, genetics, and diabetes on ARC, with potential to identify high-risk individuals for targeted interventions.</jats:p

Causal association between snoring and stroke: a Mendelian randomization study in a Chinese populationResearch in context

Summary: Background: Previous observational studies established a positive relationship between snoring and stroke. We aimed to investigate the causal effect of snoring on stroke. Methods: Based on 82,339 unrelated individuals with qualified genotyping data of Asian descent from the China Kadoorie Biobank (CKB), we conducted a Mendelian randomization (MR) analysis of snoring and stroke. Genetic variants identified in the genome-wide association analysis (GWAS) of snoring in CKB and UK Biobank (UKB) were selected for constructing genetic risk scores (GRS). A two-stage method was applied to estimate the associations of the genetically predicted snoring with stroke and its subtypes. Besides, MR analysis among the non-obese group (body mass index, BMI <24.0 kg/m2), as well as multivariable MR (MVMR), were performed to control for potential pleiotropy from BMI. In addition, the inverse-variance weighted (IVW) method was applied to estimate the causal association with genetic variants identified in CKB GWAS. Findings: Positive associations were found between snoring and total stroke, hemorrhagic stroke (HS), and ischemic stroke (IS). With GRS of CKB, the corresponding HRs (95% CIs) were 1.56 (1.15, 2.12), 1.50 (0.84, 2.69), 2.02 (1.36, 3.01), and the corresponding HRs (95% CIs) using GRS of UKB were 1.78 (1.30, 2.43), 1.94 (1.07, 3.52), and 1.74 (1.16, 2.61). The associations remained stable in the MR among the non-obese group, MVMR analysis, and MR analysis using the IVW method. Interpretation: This study suggests that, among Chinese adults, genetically predicted snoring could increase the risk of total stroke, IS, and HS, and the causal effect was independent of BMI. Funding: National Natural Science Foundation of China, Kadoorie Charitable Foundation Hong Kong, UK Wellcome Trust, National Key R&D Program of China, Chinese Ministry of Science and Technology

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations

Aims Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition. Methods and results In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45–0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67–0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66–0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08–1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71–7.60); P = 7.3 × 10−4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38–2.54); P = 5.4 × 10−5] and self-reported asthma [pooled OR of 1.17 (1.04–1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI. Conclusion The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections